Abstract
Purpose:
Apoptosis in irradiated normal lung tissue has been observed several weeks after radiation. However, the signaling pathway propagating cell death after radiation remains unknown.
Methods and materials:
C57BL/6J mice were irradiated with 15 Gy to the whole thorax. Pro-apoptotic signaling was evaluated 6 weeks after radiation with or without administration of AEOL10150, a potent catalytic scavenger of reactive oxygen and nitrogen species.
Results:
Apoptosis was observed primarily in type I and type II pneumocytes and endothelium. Apoptosis correlated with increased PTEN expression, inhibition of downstream PI3K/AKT signaling, and increased p53 and Bax protein levels. Transforming growth factor-β1, Nox4, and oxidative stress were also increased 6 weeks after radiation. Therapeutic administration of AEOL10150 suppressed pro-apoptotic signaling and dramatically reduced the number of apoptotic cells.
Conclusion:
Increased PTEN signaling after radiation results in apoptosis of lung parenchymal cells. We hypothesize that upregulation of PTEN is influenced by Nox4-derived oxidative stress. To our knowledge, this is the first study to highlight the role of PTEN in radiation-induced pulmonary toxicity.
Copyright © 2012. Published by Elsevier Inc.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Alveolar Epithelial Cells / physiology
-
Alveolar Epithelial Cells / radiation effects
-
Animals
-
Antioxidants / pharmacology
-
Apoptosis / drug effects
-
Apoptosis / physiology*
-
Caspase 3 / metabolism
-
Endothelium / physiopathology
-
Endothelium / radiation effects
-
Female
-
In Situ Nick-End Labeling / methods
-
Lung / radiation effects*
-
Lung Injury / drug therapy
-
Lung Injury / metabolism
-
Lung Injury / physiopathology*
-
Metalloporphyrins / pharmacology
-
Mice
-
Mice, Inbred C57BL
-
Models, Animal
-
NADPH Oxidase 4
-
NADPH Oxidases / metabolism
-
Oxidative Stress / drug effects
-
Oxidative Stress / physiology*
-
PTEN Phosphohydrolase / metabolism*
-
Phosphatidylinositol 3-Kinases / metabolism
-
Protein Serine-Threonine Kinases / metabolism
-
Proto-Oncogene Proteins c-akt / metabolism
-
Radiation Injuries / drug therapy
-
Radiation Injuries / metabolism
-
Radiation Injuries / physiopathology*
-
Random Allocation
-
Reactive Oxygen Species / metabolism
-
Signal Transduction / drug effects
-
Signal Transduction / physiology
-
Signal Transduction / radiation effects
-
Time Factors
-
Transforming Growth Factor beta1 / metabolism
-
Tumor Suppressor Protein p53 / metabolism
-
Up-Regulation
-
bcl-2-Associated X Protein / metabolism
Substances
-
AEOL 10150
-
Antioxidants
-
Metalloporphyrins
-
Reactive Oxygen Species
-
Transforming Growth Factor beta1
-
Tumor Suppressor Protein p53
-
bcl-2-Associated X Protein
-
NADPH Oxidase 4
-
NADPH Oxidases
-
Nox4 protein, mouse
-
integrin-linked kinase
-
Protein Serine-Threonine Kinases
-
Proto-Oncogene Proteins c-akt
-
PTEN Phosphohydrolase
-
Pten protein, mouse
-
Caspase 3